A treatment developed by the UC Berkeley Nomura Research Group and Swiss pharmaceutical giant Novartis prevents the degradation of protein molecules.
Published by Nature on Feb. 24, the research tackles protein degradation, reducing the chance of disease formation and ensuring protein molecules are more receptive to disease-fighting medication. Traditionally, various diseases have been considered “undruggable,” because medication requires “binding pockets,” or a connection point on the proteome, which is the complete set of protein molecules found in the body. However, these pockets are not well defined on degraded protein molecules, according to chemical biology professor Daniel Nomura, who runs the lab.
“My lab has been interested in developing and applying chemical biology approaches to tackle the ‘undruggable’ proteome,” Nomura said in an email. “The ‘undruggable’ proteome is one of the biggest bottlenecks that we face in developing new disease cures.”
This research was a collaborative effort between Novartis scientists and various student researchers led by campus chemical biology graduate students Nathaniel Henning and Lydia Boike, according to Nomura.
To tackle the undruggable proteome, researchers utilized deubiquitinase-targeting chimeras, or DUBTACs, a chemical that binds to protein molecules and removes ubiquitin chains, responsible for the degradation. According to a UC Berkeley College of Chemistry press release, removing ubiquitin chains makes medication more effective.
“There are many diseases, including cancer, various genetic disorders, and neurodegenerative diseases, that are caused by aberrant degradation of a protein,” Nomura said in the email. “DUBTACs enable this targeted protein stabilization.”
The researchers utilized cystic fibrosis as a case study for their treatment. Lumacaftor, an existing medication used to treat the disease does not stop protein degradation, and the team wanted to see if DUBTACs would make Lumacaftor more effective and stabilize protein from degradation, which it did.
Nomura added the team is not currently aware of any negative issues with the proteins they targeted in their study.
“Ultimately, we envision DUBTACs to be administered as oral pills for whatever disease indications we go after,” Nomura said in the email.
The Novartis-Berkeley Center for Proteomics and Chemistry Technologies, which facilitated this research, was established with the goal of developing treatments for undruggable diseases, according to a 2017 Novartis press release.
Novartis and the University of California have filed a “patent application” on this discovery, but Nomura declined to elaborate as the “terms are confidential.” The Daily Californian identified two patents between the university and Novartis, including one approved in 2021 regarding the targeting of “protein degraders.”
According to the UC Berkeley College of Chemistry website, in fiscal year 2021, Novartis’ financial contribution exceeded $1 million. Novartis has been a “lifetime” donor for more than a decade, which requires a minimum of $100,000 a year.
A representative from Novartis declined to answer questions related to intellectual property agreements and how much funding the company gives.
“With the development of the DUBTAC approach, we can now envision going after a whole class of previously ‘undruggable’ proteins and incurable diseases,” Nomura said.